There is a way to diagnose a liver disease estimated to affect tens of millions of Americans, but it requires a giant needle. Liver biopsy is considered the gold standard for detecting nonalcoholic steatohepatitis (NASH), a condition in which fat buildup in the liver leads to swelling, scar tissue, and, in severe cases, cirrhosis. However, there are growing concerns that without better diagnostic tools, many patients may not be able to access NASH drugs in the coming years.

"There is a very strong effort right now to try to diagnose NASH without a biopsy, using every means necessary or possible," said Scott Friedman, head of the liver disease division at the Icahn School of Medicine at Mount Sinai. Friedman, along with more than a dozen physicians, analysts, and industry executives interviewed by BioPharma Dive, noted that while biopsies are a valuable source of information, they have many drawbacks. They are invasive and expensive, often costing thousands of dollars. Although generally safe, there is a small risk of infection and accidental damage to other organs. The procedure can also be painful, which may deter patients, as NASH is usually asymptomatic until later stages.

However, even if the estimated 10 million to 30 million Americans with NASH agreed to undergo biopsies, there are not enough liver specialists to perform them. As of April 2018, the American Board of Internal Medicine had about 16,400 gastroenterologists with active certifications, only a small fraction of whom perform liver biopsies. Therefore, healthcare providers expect that liver biopsy will pose a significant barrier to the adoption of any approved NASH drug, especially if payers require the test as a condition for coverage and reimbursement. This could dampen the industry's enthusiasm for NASH drugs generating billions of dollars in revenue for pharmaceutical companies.

"This is exactly what we all worry about, including people in the pharmaceutical industry," said Douglas Dieterich, professor of medicine in the liver disease division at the Icahn School of Medicine at Mount Sinai.

The side effect of having no drugs

Physicians and analysts generally believe that when the first wave of NASH drugs hits the market, which could be as early as 2020, the first patients to receive treatment will be those with severe liver scarring. Conversely, for patients with milder fibrosis, drug therapy may not be the first-line option. Therefore, determining a patient's fibrosis stage is crucial, both for doctors hoping to identify the sickest patients and for companies trying to understand the size of the early NASH market. Biopsy has been the best identification tool so far, but it has not been widely adopted among some physicians.

"Without a treatment, it's hard to justify rushing to screen everyone," said Friedman, who also consults for more than twenty companies developing liver drugs or devices. Zachary Henry, a hepatologist at the University of Virginia Health System, holds a similar view. In his practice at a weight management and general liver disease clinic, he tries to avoid biopsies unless he suspects a patient has advanced fibrosis and might benefit from participating in a clinical trial. Henry explained that with no approved drugs on the market, the recommended treatment for most NASH patients is the same: better diet and more exercise. "Right now, treatment options are essentially limited to lifestyle changes, and a liver biopsy wouldn't really change that," he said.

Brent Teti at Saint Louis University Hospital clinics said he sees 15 to 20 NASH patients per week and frequently performs biopsies, although his practice is somewhat biased because it attracts patients interested in participating in clinical trials. Nevertheless, Teti told BioPharma Dive that he typically takes one of two approaches with suspected NASH patients: either warn that a biopsy will be needed if lifestyle changes are not made, or perform a biopsy to convince them they are heading toward cirrhosis.

"The NASH market, if we want to reach its potential, has to move away from liver biopsy."

—Dean Hum, Chief Operating Officer of GenFit

Fewer biopsies mean more fragmented data on the proportion of simple fat tissue versus more severe liver damage in the NASH population. Without this data, doctors or pharmaceutical companies struggle to know the number of patients who most need—and would most likely accept—NASH drugs. "We can't even scratch the surface of risk-stratifying patients with liver biopsy," Manal Abdelmalek, professor of medicine at Duke University, said in an interview. "There aren't enough providers or enough liver biopsies in this country to make a dent in the at-risk population." And the lack of biopsy data could spell trouble for pharmaceutical companies hoping to enter the NASH market, which some on Wall Street now predict will see slower growth and lower profits than initially optimistic estimates.

Notably, the National Institute of Diabetes and Digestive and Kidney Diseases, which funds the NASH Clinical Research Network, has no statistics on the number of NASH patients in the U.S. or those with its precursor condition NAFLD, nor data on NASH patients by fibrosis stage. Despite the need for more data, SVB Leerink analyst Pasha Sarraf does not expect a rapid increase in liver biopsy usage in the near term. He believes healthcare systems are unlikely to "be willing to pay for or be prepared to accept all the risks associated with performing thousands more of these procedures." "To prescribe these drugs, we have to replace biopsy as the gold standard with something else," Sarraf said in an interview.

Alternatives better than a big needle

Alternatives may not be far off. Teti at Saint Louis University expects noninvasive diagnostics like a NASH blood test to become available within the next three to five years. Friedman at Mount Sinai shares this view. GenFit, one of the few companies with a NASH drug in late-stage testing, is developing such a blood test. It measures levels of a biomarker, two proteins, and microRNA, then feeds the data into an algorithm to generate a score. A sufficiently high score would indicate that a patient is suitable for NASH treatment.

The test was developed using patient data from the company's Phase II trial of its drug elafibranor, which ultimately failed, and was later validated based on the first 500 patients screened in the ongoing Phase III study, said Dean Hum, GenFit's Chief Operating Officer. GenFit plans to seek regulatory approval for the test in 2020 and recently partnered with LabCorp's Covance business to commercialize it. Even if elafibranor is unsuccessful, GenFit envisions the test being compatible with other drugs. Hum said his company estimates that for a large chronic metabolic disease like NASH, the commercial opportunity for diagnostics is about 10% of that for therapeutic drugs. Other companies working on noninvasive NASH tools, such as blood, imaging, and functional tests, include Nordic Bioscience, Perspectum Diagnostics, and Glympse Bio.

Some diagnostic tools already in use are helpful in identifying the sickest NASH patients. Gilead said last month that in a mid-stage study of an experimental drug for liver damage caused by NASH, a combination of a blood test called ELF and an imaging tool called FibroScan accurately identified advanced fibrosis in more than 80% of participants. However, FibroScan and other currently available noninvasive tests are not as good at diagnosing "intermediate" patients. Multiple physicians told BioPharma Dive that alternatives to liver biopsy must be able to pinpoint where a patient is in the progression of NASH, providing information on fat, inflammation, and scarring.

Some are impressed by an imaging tool called magnetic resonance elastography (MRE), which can show the stiffness of liver tissue. Henry at UVA Health System said MRE "is probably a better test than FibroScan," but "it's not really clinically available right now." "Most insurance companies won't pay for it, but it's part of almost every ongoing research trial," he said.